2,4-Dichloro-1-nitrobenzene 1,4-dichloro-2-nitrobenzene Evaluation of the carcinogenicity and genotoxicity To: the State Secretary of Social Affairs en Employment No. 2018/24, The Hague, December 11, 2018 2 2 Contents 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 2 of 40 contents Samenvatting 3 05 2,4-dichloro-1-nitrobenzene 13 5.1 Genotoxicity 14 Executive summary 4 5.2 Carcinogenicity 17 01 Scope 5 06 1,4-dichloro-2-nitrobenzene 22 1.1 Background 6 6.1 Genotoxicity 23 1.2 Committee and procedure 6 6.2 Carcinogenicity 27 1.3 Data 6 Literature 30 02 Identity of the substances 7 2.2 Physico-chemical properties 8 Annexes 33 A Classification on carcinogenicity 34 03 Manufacture and uses 9 B Classification on mutagenicity 34 3.1 Manufacture 10 C Criteria for testing reliability of animal and in vitro studies 37 3.2 Identified uses 10 04 Summary of toxicokinetics 11 1 Health Council of the Netherlands | No. 2018/24 2 3 Samenvatting 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 3 of 40 Advies aan de staatssecretaris samenvatting Op grond van de beschikbare wetenschappelijke gegevens concludeert de commissie dat Op verzoek van de Minister van Sociale zaken pigmenten, pesticiden en medicinale drugs. 2,4-dichloor-1-nitrobenzeen en 1,4-dichloor-2- en Werkgelegenheid (SZW) heeft de 1,4-Dichloor-2-nitrobenzeen wordt gebruikt als nitrobenzeen beschouwd moeten worden als Gezondheidsraad de genotoxische en intermediair in de synthese van pigmenten, kankerverwekkend voor de mens. Ze adviseert kankerverwekkende eigenschappen beoordeeld pesticiden en UV absorbers. de stof in te delen in gevarencategorie 1Ba. De van 2,4-dichloor-1-nitrobenzeen en 1,4-dichloor- twee stoffen kunnen kanker veroorzaken via een 2-nitrobenzeen (in dit advies kortweg aangeduid Classificeren op basis van bewijskracht stochaststisch genotoxisch als dichloornitrobenzenen). Dit advies is tot voor schadelijk effect werkingsmechanisme. stand gekomen in de Subcommissie De commissie beoordeelt of er aanwijzingen zijn Classificatie van carcinogene stoffen, een dat de stof genotoxisch en kankerverwekkend is Voor mutageniteit adviseert de commissie om subcommissie van de Commissie Gezondheid voor mensen. Als dat zo is, stelt de commissie de stoffen niet in te delen in een en Beroepsmatige Blootstelling aan Stoffen voor om de stof in te delen in gevarencategorie. Er zijn onvoldoende (GBBS). gevarencategorieën, één die aangeeft hoe groot gegevens beschikbaar over de mutagene Op www.gezondheidsraad.nl staat informatie de bewijskracht is dat de stof mutageen is in de effecten van de stoffen in geslachtscellen. over de taken van deze vaste commissie van de geslachtscellen (dat wil zeggen: erfelijk Gezondheidsraad. De samenstelling van de overdraagbare mutaties kan veroorzaken) en commissie is te vinden achterin dit advies. één die aangeeft hoe groot de bewijskracht is dat de stof tot kanker kan leiden. De categorieën Gebruik van dichloornitrobenzenen zijn afgeleid van EU-verordening (EG) 2,4-Dichloor-1-nitrobenzeen wordt onder meer 1272/2008. gebruikt als intermediair in de synthese van a Zie Annex A (carcinogeniteit) en B (mutageniteit) voor classificatiesysteem. 2 Health Council of the Netherlands | No. 2018/24 2 4 Executive summary 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 4 of 40 may act by a stochastich genotoxic mechanism executive summary of action. At request of the Minister of Social Affairs and Classification according to strength of Based on insufficient data, the Committee does Employment, the Health Council of the evidence for toxic effect not recommend a classification as germ cell Netherlands evaluates and judges the genotoxic For the judgement on the carcinogenic mutagens. and carcinogenic properties of substances to properties of a substance, the Committee uses a which workers are occupationally exposed. classification system, which is largely based on The evaluation is performed by the EU-Directive 1272/2008. In addition to SubCommittee on Classifying Carcinogenic classifying substances on carcinogenicity, the Substances of the Dutch Expert Committee on Committee also assesses the genotoxic Occupational Safety of the Health Council, properties. hereafter called the Committee. In this report, the Committee evaluated 2,4-dichloro-1- Recommendations to the State Secretary nitrobenzene and 1,4-dichloro-2-nitrobenzene. Based on the available scientific data, the Committee concludes that 2,4-dichloro-1- Identified uses nitrobenzene and 1,4-dichloro-2-nitrobenzene 2,4-Dichloro-1-nitrobenzene is used as an are presumed to be carcinogenic to man, and intermediate for the synthesis of pigments, recommends classifying both compounds in pesticides and medicinal drugs. 1,4-Dichloro-2- category 1Ba (the substances are presumed to nitrobenzene is used as an intermediate for the be carcinogenic to humans). The subsances synthesis of pigments, pesticides and UV absorbents. a See Annex A (carcinogenicity) and B (mutagenicity) for the classification system. 3 Health Council of the Netherlands | No. 2018/24 2 5 chapter 01 | Scope 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 5 of 40 01 scope 4 Health Council of the Netherlands | No. 2018/24 2 6 chapter 01 | Scope 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 6 of 40 1.1 Background account in deciding on the final version of the report. These comments, In the Netherlands a special policy is in force with respect to occupational and the replies by the Committee, can be found on the website of the use and exposure to carcinogenic substances. Regarding this policy, the Health Council. Minister of Social Affairs and Employment has asked the Health Council of the Netherlands to evaluate the carcinogenic properties of substances, 1.3 Data and to propose a classification. In addition to classifying substances as The evaluation and recommendation of the Committee is standardly carcinogenic, the Health Council also assesses the genotoxic properties based on scientific data, which are publicly available. The starting point of of the substance in question, and proposes a classification on germ cell the Committees’ reports is, if possible, the monographs of the International mutagenicity. Both classifications are based on the criteria set by the Agency for Research on Cancer (IARC). This means that the original European Parliament (EU Regulation No. 1272/2008), and expressed in sources of the studies, which are mentioned in the IARC-monograph, are the form of standard sentences (see Annex A and B for carcinogenicity reviewed only by the Committee when these are considered relevant in and mutagenicity, respectively). assessing the carcinogenicity and genotoxicity of the substance in This report contains the evaluation of the carcinogenicity and germ cell question. However, in the case of 2,4-dichloro-1-nitrobenzene and mutagenicity of 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2- 1,4-dichloro-2-nitrobenzene, such an IARC-monograph is not available. nitrobenzene. In addition, published data were retrieved from the online databases Medline, Toxline, and Chemical Abstracts covering the period to June 1.2 Committee and procedure 2018 using 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene The evaluation is performed by the Subcommittee on Classifying as keywords, in combination with keywords representative for carcinogenic substances of the Dutch Expert Committee on Occupational carcinogenesis and mutagenesis. Safety of the Health Council, hereafter called the Committee. The members of the Committee are listed on the last page of this advisory report . In 2018, the President of the Health Council released a draft of the report for public review. The Committee has taken the comments received into 5 Health Council of the Netherlands | No. 2018/24 2 7 chapter 02 | Identity of the substances 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 7 of 40 02 identity of the substances 6 Health Council of the Netherlands | No. 2018/24 2 8 chapter 02 | Identity of the substances 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene | page 8 of 40 Property 2,4-dichloro-1- 1,4-dichloro-2- Comment Ref. nitrobenzene Value nitrobenzene Value 2.1 Name and other identifiers of the substances Melting point 34 °C 53-56 °C 1-3 The identity and some physicochemical properties of 2,4-dichloro-1- Boiling point 258 °C at1.013 hPa 261-267 °C at 1.013 hPa 1-3 Relative density 1.4790 at 80 °C; nitrobenzene and 1,4-dichloro-2-nitrobenzene are given in Tables 1 and 2 1.669 at 22 °C 1-3 (air = 1) 1.54 at 15 °C 1-3 below. 68.9 mg/L at 25 °C; 200 Solubility in water 95 mg/L at 25 °C (meas.) 1-3 mg/L at 25 °C (meas.) Soluble in ethanol, ether, Soluble in ethanol and Table 1. Substance identity and information related to molecular and structural formula Solubility in organic benzene, carbon disulfide; ether; slightly soluble in 1-3 of the substances solvents slightly soluble in carbon chloroform tetrachloride 2,4-dichloro-1-nitrobenzene 1,4-dichloro-2-nitrobenzene Log P (n-octanol/ 3.07 (not further specified); Chemical name 2,4-dichloro-1-nitrobenzene 1,4-dichloro-2-nitrobenzene 2.93 at 25 °C (meas.) 1-3 water) 2.90 at 25 °C (meas.) IUPAC name 2,4-dichloro-1-nitrobenzene 1,4-dichloro-2-nitrobenzene 1.0 Pa at 25 °C (meas.); EC number 210-248-3 201-923-3 Vapour pressure 0.51 Pa at 25 °C (meas.) 1-3 1.91 Pa at 25 °C (calc) RTECS number CZ5420000 [RTECS] CZ5260000 [RTECS] 3 3 Conversion factor 1 ppm = 7.85 mg/m air at 1 ppm = 7.85 mg/m air at 1-3 CAS registry number: 611-06-3 89-61-2 (20 °C, 101.3 kPa) 20 °C; 1 mg/m3 = 0.127 ppm 20 °C; 1 mg/m3 = 0.127 ppm Synonyms 2,4-dichloronitrobenzene, 2,5-dichloronitrobenzene 1,3-dichloro-4-nitrobenzene Nitro-p-dichlorobenzene asym.-Nitro-m-dichlorobenzene 2.3 International classifications Molecular formula C6H3Cl2NO2 C6H3Cl2NO2 Structural formula European Commission No harmonized classification is available for 2,4-dichloro-1-nitrobenzene and 1,4-dichloro-2-nitrobenzene.